University of Kentucky UKnowledge Molecular and Cellular Biochemistry Faculty Molecular and Cellular Biochemistry Patents 1-23-2018 Arylquinoline and Analog Compounds and Use Thereof to Treat Cancer David S. Watt University of Kentucky, [email protected] Chunming Liu University of Kentucky, [email protected] Vivek M. Rangnekar University of Kentucky, [email protected] Vitaliy M. Sviripa University of Kentucky, [email protected] Ravshan Burikhanov University of Kentucky, [email protected] See next page for additional authors Right click to open a feedback form in a new tab to let us know how this document benefits oy u. Follow this and additional works at: https://uknowledge.uky.edu/biochem_patents Part of the Medical Biochemistry Commons Recommended Citation Watt, David S.; Liu, Chunming; Rangnekar, Vivek M.; Sviripa, Vitaliy M.; Burikhanov, Ravshan; and Zhang, Wen, "Arylquinoline and Analog Compounds and Use Thereof to Treat Cancer" (2018). Molecular and Cellular Biochemistry Faculty Patents. 25. https://uknowledge.uky.edu/biochem_patents/25 This Patent is brought to you for free and open access by the Molecular and Cellular Biochemistry at UKnowledge. It has been accepted for inclusion in Molecular and Cellular Biochemistry Faculty Patents by an authorized administrator of UKnowledge. For more information, please contact [email protected]. Authors David S. Watt, Chunming Liu, Vivek M. Rangnekar, Vitaliy M. Sviripa, Ravshan Burikhanov, and Wen Zhang This patent is available at UKnowledge: https://uknowledge.uky.edu/biochem_patents/25 I IIIII IIIIIIII Ill lllll lllll US009873670B2lllll lllll lllll lllll lllll lllll 111111111111111111 c12) United States Patent (IO) Patent No.: US 9,873,670 B2 Watt et al. (45) Date of Patent: Jan.23,2018 (54) ARYLQUINOLINE AND ANALOG C07D 495/04 (2006.01) COMPOUNDS AND USE THEREOF TO C07D 2151227 (2006.01) TREAT CANCER C07D 215/36 (2006.01) (52) U.S. Cl. (71) Applicant: UNIVERSITY OF KENTUCKY CPC ............ C07D 215/38 (2013.01); A61K 31147 RESEARCH FOUNDATION, (2013.01); C07D 215/06 (2013.01); C07D Lexington, KY (US) 2151227 (2013.01); C07D 215/36 (2013.01); C07D 495/04 (2013.01) (72) Inventors: David S. Watt, Lexington, KY (US); (58) Field of Classification Search Chunming Liu, Lexington, KY (US); CPC ............................ C07D 215/38; C07D 215/06 Vivek Rangnekar, Nicholasville, KY See application file for complete search history. (US); Vitaliy M. Sviripa, Lexington, KY (US); Ravshan Burikhanov, (56) References Cited Lexington, KY (US); Wen Zhang, U.S. PATENT DOCUMENTS Lexington, KY (US) 2007/0077644 Al 4/2007 Yoshio (73) Assignee: University of Kentucky Research Foundation, Lexington, KY (US) FOREIGN PATENT DOCUMENTS ( *) Notice: Subject to any disclaimer, the term ofthis WO 2009/127417 Al 10/2009 patent is extended or adjusted under 35 U.S.C. 154(b) by O days. OTHER PUBLICATIONS (21) Appl. No.: 15/036,916 Walser et al., J. Heterocyclic Chemistry (1975), 12(2), 351-8. Mphahlele et al., Molecules (2011), 16, 8958-8972. (22) PCT Filed: Nov. 21, 2014 L. Fu et al., "Novel and efficient synthesis of substituted quinoline- 1-oxides and the complex compounds SnL2Cl2 (L�2- aminoquinoline-l-oxides) with the aid of stannous chloride," Tet­ (86) PCT No.: PCT/US2014/066796 rahedron 68 (2012), 7782-7786. § 371 (c)(l), Burikhanov et al., "Arylquins target vimentin to triggar Par-4 (2) Date: May 16, 2016 secretion for tumor cell apoptosis," Nature Chemical Biology, Sep. 14, 2014, vol. 10, No. 11, pp. 924-926. International Search Report and Written Opinion issued in Appli­ (87) PCT Pub. No.: W02015/077550 cation No. PCT/US2014/066796 dated Feb. 15, 2015. PCT Pub. Date: May 28, 2015 Primary Examiner - Samira Jean-Louis (65) Prior Publication Data (74) Attorney, Agent, or Firm - McDermott Will & Emery LLP US 2016/0280652 Al Sep. 29, 2016 (57) ABSTRACT Related U.S. Application Data The subject technology relates to arylquinoline compounds (60) Provisional application No. 61/907,817, filed on Nov. and their use for treating cancer or cancer metastasis. The 22, 2013. compounds of the subject technology promote cells to secrete a pro-apoptotic tumor suppressor, i.e., prostate apop­ (51) Int. Cl. tosis response-4 (Par-4), which in tum promote apoptosis in C07D 215/38 (2006.01) cancer cells or metastatic cells. C07D 215/06 (2006.01) A61K 31147 (2006.01) 13 Claims, 5 Drawing Sheets U.S. Patent Jan.23,2018 Sheet 1 of 5 US 9,873,670 B2 X = ortho-F, Y = NMe (Arylquin 1) = = 2 X meta-F, Y NMe2 (Arylquin 2) = = N 3 X para-F, Y Me2 (Aryl1uin ) X = H, Y = NMe2 (Arylquin l X = ortho-F, Y = H (Arylquin 8) ..__...e, f = 4 Z O (Arylquin ) .......i-- 6 Z = S (Arylquin 5) , c Arylquin : I di H N 0 0 NH S� ri2 \12 ri2 O Biotinylated Arylquin 9 O ° 3 b, Legend of reagents: a, arylacetonitrile, terl-BuOK,DMF, 90 C, -4h; ° 2(2'­ c, fluorophenyl)acetyl chloride, Et3N, reflux2h and then K2C03, DMF, 90 C, 4h; 2,4-bis(4- methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (Lawesson's reagent), dioxane, d, 0 reflux 5h; (+)-biotinyl-iodoacetamidyl-°3,6-dioxaoctanediamine, K2C 3, DMF, 12h; e, POCl3, reflux, 3h; f,Zn, CH3C02H, 75 C, 1 h. FIG.1 U.S. Patent Jan.23,2018 Sheet 2 of 5 US 9,873,670 B2 80 ** t,. PC-3 60 D H1299 -� o HOP92 g- 40 ¢ HEL CLco 2f2- 20 o ...........---� V 0.5 1 10 [Arylquin 1] (µM) oPC-3 MM2 8 11H 6 80 oLLC-1 80 0 4 0 ** 11 DU145 oA549 ** oWTMEF a LNCaP U) 6 11KP7B 6 -� 60 o BEC - 0 -� 0 v ** HEL � a p53·/- MEF PrE 40 o ** g-40 i40 o PrS ** JCL ::t * � 2f2- 20 � 20 2f2- 20 o�---.---.---, V 0.5 1 10 V 0.5 1 10 V 0.5 1 10 Arylquin 1 (µM) Arylquin 1 (µM) Arylquin 1 (µM) FIG. 2 U.S. Patent Jan.23,2018 Sheet 3 of 5 US 9,873,670 B2 50 n E:'21 Vehicle � Arylquin 1 40 �=­ 30 C) '#.cu 20 10 o..U..:..t:....,;L.t:....,;L..lll....J..'--ll.ul'--ll.ulilU...J�.iL..L.;J.;U....l:....;J.;..lll....J..�L...L..(;JilU...J�.iL..L...L.l.(..L..L.l.(..L�HEL H1299 HOP92 A549 H460 PC-3 HEL H1299 HOP92 A549 H460 PC-3 Par-4-expressing Par-4-null MEFs co-culture MEFs co-culture ** n 50 ** ** r, 40 0Vehicle -�=­ 30 IZJArylquin1 C) '#.g- 20 10 o�..&.:..:.L.-L...;t;.:.i.._..i...:.i..:.;.L......L�-L..�...J..a.;4-�-L�HEL H1299 HOP92 A549 H460 No Con Par-4 Antibody PC-3 MM2 Mouse serum treatment FIG. 3 U.S. Patent Jan.23,2018 Sheet 4 of 5 US 9,873,670 B2 80 c:: KP-78 LLC-1 H460 A549 H1299 0 ** ·u5en � 60 (l) 00r-- ci.. et:: <!) 40 (l) 0 � en= (l) 0 20 �0 0 Par-4·/· + V + + + + + Par-4·/· + Aq + + + + + CM from + + Par-4 / + V + + + + + Par-4+/+ + Aq 60 KP-78 LLC-1 H460 A549 H1299 ** ** en ·u5 40 .9 ** ·.:·· =- ·.:···. :::::: =-0 �0 :{ 20 :}·.:···. 0 Par-4·/· + Aq C c c c c + CM Par-4·/· Aq + · G G G G G + + Ab· from Par-4 / + Aq c c c c c Par-4+/+ + Aq G G G G G FIG.4 U.S. Patent Jan.23,2018 Sheet 5 of 5 US 9,873,670 B2 75 ** ** c:: en ·u5 %2 =­ 5 <( Q+-=aa;;aa-----=a,,aaaaa----=aa,a=-----'=a,aaa--- Vim+/+ Vim·/- Par -4 Ab lgG Ab Vim·/- FIG. 5 US 9,873,670 B2 1 2 ARYLQUINOLINE AND ANALOG ment of cancer or for the treatment or inhibition of cancer COMPOUNDS AND USE THEREOF TO metastasis in a subject in need thereof comprising adminis­ TREAT CANCER tering to the subject an effectiveamount of the compound or a pharmaceutically acceptable salt thereof or a composition CROSS-REFERENCE TO RELATED 5 thereof. Other advantages of the subject technology include com­ APPLICATION pounds for use in promoting the secretion of Prostate Apoptosis Response-4 (PAR-4) from cells or for use in This application is a U.S. National Phase under 35 U.S.C. promoting apoptosis of a cancer cell in a subject comprising §371 oflnternational Application No. PCT/US2014/066796, administering to the subject an effective amount of an 10 filed Nov. 21, 2014, which claims the benefit of U.S. arylquinoline or analog compound or a pharmaceutically Provisional Application No. 61/907,817, filed Nov. 22, acceptable salt thereof or a composition thereof. 2013, the entire disclosures of which are hereby incorpo­ In one aspect of the subject technology, the arylquinoline rated by reference herein. is a compound according to Formula (I): STATEMENT REGARDING FEDERALLY 15 SPONSORED RESEARCH (I) This work was supported by National Center for Research Resources in a grant entitled "COBRE Center for Biomedi- cal Research Excellence" grant P20 RR020171; and NIH/ 20 NCI ROI CA60872 (to VMR). The government has certain rights in the subject technology. TECHNICAL FIELD or a pharmaceutically acceptable salt thereof; wherein n is 1, 25 2, 3, 4, 5, or 6, for each NR1 R2, R1 and R2 are independently The present invention relates to compounds that treat H, alkyl, alkoxy, aryl, heteroaryl; Ar is aryl or heteroaryl, cancer and/or treat or prevent cancer metastasis. In particu­ which can be further substituted with halogen, amino, alky­ lar, the subject technology is directed to arylquinoline com­ lamino, dialkylamino, arylalkylamino, N-oxides of dialky­ pounds and analogs thereof such as arylquinolone or aryl­ lamino, trialkylammonium, mercapto, alkylthio, alkanoyl, thioquinolone compounds, described as "arylquin" 30 nitro, nitrosyl, cyano, alkoxy, alkenyloxy, aryl, heteroaryl, compounds, that promote cells to secrete a pro-apoptotic sulfonyl, sulfonamide, CONR3R4, NR3CO(R4), NR3COO tumor suppressor, such as prostate apoptosis response-4 (R4), NR3CONR4R5 where R3, R4, R5, are independently, H, (Par-4), which promotes apoptosis in cancer cells or meta­ alkyl, aryl, heteroaryl or a fluorine; X represents halogen; m static cells.